What are the guidelines for using methotrexate (MTX) and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) together in therapy?

Methotrexate and NSAID Therapy: Guidelines for Combined Use

NSAIDs can be given concurrently with low-dose methotrexate in patients with normal renal function, but caution is needed due to potential interactions that may increase methotrexate toxicity. 1

Safety of Combined Therapy

• NSAIDs can reduce renal elimination of methotrexate, potentially leading to toxicity, with case reports documenting significant morbidity and mortality following co-prescription of certain NSAIDs and methotrexate 1
• The British Association of Dermatologists guidelines note that drug interactions with methotrexate usually occur due to altered pharmacokinetics, such as displacement of protein binding and reduced renal elimination 1
• Patients should be made aware of the need to report features of methotrexate toxicity such as mouth ulceration and any changes in prescription including concomitant use of NSAIDs 1

Mechanism of Interaction

• NSAIDs can reduce renal elimination of methotrexate, leading to increased serum levels and potential toxicity 1
• The glucuronides of NSAIDs, as well as parent compounds, can inhibit methotrexate excretion via multidrug resistance proteins (MRP2 and MRP4) in a stereoselective and concentration-dependent manner 2
• The interaction may also involve displacement of methotrexate from plasma proteins or competition for renal tubular excretion 3

Specific Recommendations for Combined Use

• In pediatric patients, NSAIDs or salicylates can be given concurrently with low-dose methotrexate in children with normal renal function (Strength of Recommendation B, Level of Evidence II) 1
• Anti-inflammatory doses of aspirin should be avoided with methotrexate due to increased risk of toxicity 4
• Patients with risk factors such as renal insufficiency or advanced age may need closer monitoring when using methotrexate, especially with concurrent NSAID use 1
• Methotrexate dosage should be reduced in those with suboptimal renal function, and avoided in patients on dialysis or with creatinine clearance <20 mL/min 1

Monitoring Recommendations

• Patients on both methotrexate and NSAIDs should have more frequent monitoring of:

  • Complete blood count (CBC) to detect bone marrow suppression 5
  • Liver function tests to monitor for hepatotoxicity 1
  • Renal function tests, especially in elderly patients or those with pre-existing renal impairment 1

• Withhold or decrease methotrexate dose if:

  • Total white blood cell count <3 × 10^9/L 1
  • Neutrophils <10 × 10^9/L 1
  • Platelets <100,000/L 1
  • Liver enzymes ≥3 × upper limit of normal for 2 consecutive months 1

Specific NSAID Considerations

• Case reports have documented toxicity particularly with naproxen, diclofenac, ibuprofen, and indomethacin when combined with methotrexate 1
• The FDA label for methotrexate specifically warns that "unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs)" 5
• Not all NSAIDs interact with methotrexate to the same degree; some studies suggest that celecoxib and etoricoxib may cause only mild adverse events when combined with methotrexate 4

Special Populations and Situations

• Elderly patients and those with reduced renal function are at higher risk for potential interactions between methotrexate and NSAIDs 1
• Intercurrent illness that induces dehydration would be a reason to omit methotrexate dosing until recovery, especially in patients also taking NSAIDs 1
• In patients with rheumatoid arthritis, the European League Against Rheumatism (EULAR) guidelines recognize NSAIDs as effective symptomatic therapies but recommend they "should be used at the minimum effective dose for the shortest time possible, after evaluation of gastrointestinal, renal and cardiovascular risks" 1

Practical Recommendations

• Perform a comprehensive medication review before initiating combination therapy to identify all potential drug interactions 1
• Consider using alternative analgesics (like acetaminophen) instead of NSAIDs in patients at high risk for methotrexate toxicity 4
• Educate patients to report any unusual symptoms promptly, particularly those suggesting methotrexate toxicity (mouth ulcers, unusual bruising, severe sore throat, dyspnea) 1
• If NSAIDs must be used with methotrexate, consider scheduling the NSAID on different days than methotrexate to minimize interaction risk 1